GENETICS AND HOMOSEXUALITY ________________________________________ Introduction Sexual orientation is one of the most distinct sex differences mammalian species

GENETICS AND HOMOSEXUALITY
________________________________________
Introduction

Sexual orientation is one of the most distinct sex differences mammalian species. With few exceptions, the majority of people are heterosexual; most males desire females as sexual partners and vice versa. Knowledge about whether someone has a sexual preference for males or females is one of the most reliable behavioral predictors of that individual’s biological sex, perhaps second only to gender identity. Although heterosexuality is the norm, a small but significant proportion of individuals (6%) report having more homosexual attractions (Diamond, 1993). The distribution of men and women between the two extremes of sexual orientation (completely heterosexual vs. completely homosexual) shows some interesting differences. Men are bimodally distributed, with most men being attracted to just one sex (Hamer, Hu, Magnuson, Hu, ; Pattatucci, 1993; Vrangalova ; Savin-Williams, 2012). On the contrary, fewer women report that they are exclusively attracted to the same sex, but more of them report attraction to both sexes compared to men (Hu et al., 1995; Vrangalova ; SavinWilliams, 2012).
Richard von Krafft-Ebing, a prominent Viennese sexologist, was among those who believed that the homosexual behavior was a result of defective development (Krafft-Ebing, 1965). By the late nineteenth and early twentieth centuries, the discourse had changed somewhat. The bodies of homosexuals were still seen as distinct, but they were now characterized as a third sex (Hirschfeld, 1958). In this framework, homosexuals were seen as inverts, that is, homosexual men were thought to have some innately feminine tendencies, while homosexual women were more inclined to express masculine traits. Although homosexuals are no longer considered a distinct sex, the inversion paradigm continues to influence the way research on homosexuality is presented, particularly in terms of neurological correlates (Berglund, Lindstrom, ; Savic, 2006; LeVay, 1991; Rice, Friberg, ; Gavrilets, 2012; Savic, Berglund, ; Lindström, 2005).
In this essay, I will consider the role of epigenetics in human sexual orientation. Firstly, I will discuss the role of genetics in influencing this trait and review significant findings from 1994 to 2014. Secondly, I will highlight findings suggesting a link between epigenetics and sexual orientation, with a particular focus on female sexual orientation and prenatal hormone exposure. Thirdly, I will consider data from animal models about potential epigenetic mechanisms that could underlie long-term or organizational effects of prenatal hormones.

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The genetics of sexual orientation
The first clues that sexual orientation, particularly in men, was strongly influenced by genetics came from family and twin studies. Gay men have a higher number of homosexual relatives in comparison to heterosexual men (Bailey ; Pillard, 1991; Pillard ; Weinrich, 1986). Similarly, in the families of nonheterosexual women, there is evidence of clustering of this trait (Pattatucci ; Hamer, 1995). Twin studies have also indicated a significant role for genetics. Although the exact concordance rates in monozygotic (MZ) twins differs between studies, they are uniformly higher than concordance rates in dizygotic (DZ) twins or nontwin siblings, and all suggest that sexual orientation is a highly heritable trait (Bailey, Dunne, ; Martin, 2000; Bailey ; Pillard, 1991; Kendler, Thornton, Gilman, ; Kessler, 2000; Kirk, Bailey, Dunne, ; Martin, 2000). There have been few molecular genetic studies in this area with the majority done by Dean Hamer’s group at the NIH. They reported the first linkage of male homosexuality to a specific genetic location in 1993 (Hamer et al., 1993). They first noticed that male homosexuality appeared to be maternally loaded (such that, gay male probands had more gay male relatives on their maternal side), which led them to focus on the X chromosome. They found that male sexual orientation was linked to a region near the end of this chromosome called Xq28, which is large, complex, and gene dense.
A meta-analysis across all four studies revealed that Xq28 allele sharing was significantly elevated among gay brothers (Hamer, 1999). Of note is that female sexual orientation does not appear to be linked to Xq28 (Hu et al., 1995). To date, two follow-ups to this group of studies have been published. Mustanski et al. (2005) performed the first genomewide scan for markers associated with male sexual orientation. Their sample group included subjects who were part of the earlier studies, and when they limited their analysis to just these individuals, they also found linkage to Xq28. When all subjects were considered, the highest linkage scores were seen at chromosomes 7 (7q36) and 8 (8p12). Interestingly, this study also observed linkage at chromosome 10 (10q26) that resulted from excess sharing of maternal alleles only. The relevance of this particular finding to the potential involvement of epigenetic mechanisms will be discussed later. In summary, this study reinforced the view that genetics plays a major role in male sexual orientation and that at least one type of male homosexuality may be inherited maternally.
A genomewide linkage scan from 2010 also used homosexual brother pairs but was unable to identify any significantly linked regions (Ramagopalan, Dyment, Handunnetthi, Rice, & Ebers, 2010). However, the number of brother pairs in this study was much smaller than in Mustanski et al. At the 2012 Annual Meeting of the American Society of Human Genetics, the results of two new genetic linkage or association studies were presented. The first study was a large-scale linkage study on 410 independent pairs of homosexual brothers from Alan Sanders, which largely agrees with the results of Mustanski et al. (Sanders et al., 2012). In this study, the strongest linkage peak was seen on chromosome 8 and overlaps with the peak seen in the 2005 study. The second strongest linkage differences in the types of subjects collected—Sanders et al. used brother pairs whereas Drabant et al. cast a much wider net. Taken together, these studies seemingly show that genetics plays a role in sexual orientation, at least for men. This is not entirely surprising. Since sexual reproduction is essential to species propagation, placing sexual orientation under genetic control would ensure tight regulation of this behavior. Nevertheless, there seems to be an additional layer of molecular control, which is likely to involve epigenetic mechanisms. Although this was the largest and best-powered genomewide association study (GWAS) on sexual orientation, it did not find any genetic markers that were significantly associated with sexual orientation (Drabant et al., 2012).

Epigenetics and sexual orientation in humans

Direct evidence of epigenetic mechanisms in human sexual orientation is sparse. There are several lines of evidence that indicate an involvement of these mechanisms but a direct link is yet to be demonstrated. In this paragraph, relevant data will be reviewed and highlight a recent hypothesis that has gained prominence about how epigenetics may help explain the occurrence of homosexuality. This will lead us into a discussion about the role of prenatal hormones in female sexual orientation and potential epigenetic mechanisms that may account for this long-term effect of prenatal hormone exposure. The first indication that epigenetic mechanisms may be involved in sexual orientation emerged from the twin studies described earlier (Bailey et al., 2000; Bailey & Pillard, 1991; Kendler et al., 2000; Kirk et al., 2000). The concordance rate between MZ twins was always higher than in DZ twins but even the highest observed rate of concordance, 52% (Bailey & Pillard, 1991), was far below what would be expected for a trait that is exclusively genetically influenced and strongly suggests a role for environmental effects in influencing sexual orientation. Many researchers increasingly believe that environmental effects are translated into biological consequences through epigenetic mechanisms (Jirtle & Skinner, 2007.

We already know that the DNA methylation profile is not identical between MZ twins at the time of birth (Gordon et al., 2012). There is also increasing evidence that discordance among MZ twins in other traits is related to DNA methylation differences (Dempster et al., 2011; Kuratomi et al., 2008). There are other clues that the in utero environment may be a player in sexual orientation. The fraternal birth order effect is one of the most replicated and robust findings in sexual orientation research. Each son increases the odds of homosexuality in the next son by 33% relative to the baseline population rate (Blanchard, 1997; Blanchard & Bogaert, 1996; Jones & Blanchard, 1998). Although this may seem like a large increase, the probability of a gay son reaches 50% only after 10 older brothers. The biological mechanism underlying fraternal birth order is still unclear. One hypothesis that has yet to be tested is that a male pregnancy triggers male-specific antigens in the mother, and each successive male child increases this immune response (Blanchard & Bogaert, 1996; Blanchard & Klassen, 1997). Whether this hypothesis or another proves accurate, it is highly probable that epigenetic mechanisms mediate the long-term consequences of the in utero events. As detailed above, Mustanski et al. (2005) observed a linkage of male homosexuality to 10q26. This chromosomal stretch is of particular interest in the context of epigenetic mechanisms as it is only linked to male sexual orientation when there is an excess sharing of alleles of maternal origin. This finding suggests the involvement of genomic imprinting. In line with this, 10q26 contains a region that is differentially methylated in the germline based on parent-of-origin (Strichman-Almashanu et al., 2002). Epigenetic mechanisms that specifically affect the X chromosome have also been implicated in sexual orientation. In individuals with two X chromosomes, one copy of the X chromosome is inactivated so that X gene

Effects of hormones on molecular mechanisms

The long-term changes in CAH women seem to originate from the prenatal exposure to high levels of testosterone. How does this one early experience continue to have ramifications throughout that individual’s life? Although we do not have a definitive answer to this question yet, recent studies in animal models have begun to shed light on this issue and strongly implicate the involvement of epigenetics. The long-term effects of prenatal hormone exposure have been studied in animal models for decades. Collectively, these effects are termed “organizational” because they appear to organize affected tissues and behaviors to develop in a particular way (Ngun, Ghahramani, Sanchez, Bocklandt, ; Vilain, 2011). On the other hand, the acute actions of hormones that rely on their continued presence, and often on an earlier organizational effect, are termed “activational.”
The initial experimental demonstration of organizational effects was a seminal study where pregnant guinea pigs were injected with testosterone resulting in their daughters showing masculinized mating behavior in adulthood (Phoenix et al., 1959). This study demonstrated the main concepts of the organizational theory of hormonal action: differentiation along sex-specific lines, apparent effects much later in life, and sensitivity during a small developmental period. Since then, sex steroids have been shown to lead to sex differences in brain gene expression, neural anatomy and morphology, and behavior (Arai ; Matsumoto, 1978; Barraclough ; Gorski, 1961; Fleming ; Vilain, 2005; Hines, Allen, ; Gorski, 1992; Kauffman et al., 2007; Murakami ; Arai, 1989; van Nas et al., 2009; Rissman, Wersinger, Taylor, ; Lubahn, 1997; Tang ; Wade, 2012).
Many testosterone-related effects with regards to brain sexual differentiation in rodents are actually dependent on its conversion to estradiol via aromatization (Naftolin, 1994). For instance, the large sex difference seen in the sexually dimorphic nucleus of the preoptic area results from the prevention of neuronal apoptosis by aromatized testosterone (Tsukahara, 2009). Testosterone and estradiol promote sexual differentiation by acting on a wide variety of cellular processes such as cell division, migration, growth, and survival to synaptic patterning (Ngun et al., 2011). It is important to keep in mind that the active hormone in organizing the brain sexually differs between humans and most animal models. In humans and other primates, androgens (and not estradiol) are the primary hormonal differentiators (Wallen, 2005). There is compelling evidence implicating the involvement of epigenetic mechanisms in mediating the long-term effects of hormones and sexual differentiation of the brain in animal models. Adult methylation patterns at the promoters of the two canonical estrogen receptors and the progesterone receptor are affected by perinatal hormones (Schwarz et al., 2010). Levels of histone acetylation in the developing cortex/hippocampus are sexually dimorphic (Tsai, Grant, ; Rissman, 2009).

In addition, regulation of histone acetylation is crucial to sexual differentiation of the principal nucleus of the Bed Nucleus of the Stria Terminalis (BNST) (Murray et al., 2009). A large number of micro-RNAs show sexually dimorphic expression in the neonatal mouse brain and early prenatal stress can lead to transgenerational dysmasculinization of mRNA expression (Morgan ; Bale, 2011; Morgan ; Bale, 2012). Data (Ghahramani et al., 2014) suggest that molecular organization by testosterone in the mouse brain occurs via early programming on relatively few genes and that this small initial effect is what sets up the brain to respond in a particular fashion to other events during postnatal development. Presently, direct demonstration of epigenetic mechanisms in mediating the long-term effects of hormones in humans has not been achieved. However, there are strong indications that environmental factors can exert long-lasting effects on the brain through DNA methylation (Hernandez et al., 2011; Ladd Acosta et al., 2007; McGowan et al., 2009), and it is known that the methylome of the human brain shows many sex differences (Lister et al., 2013).

Conclusion
The issue of whether homosexuality is linked to genes is confusing. Simon LeVey tried to prove this linkage by studying the brains (hypothalamus) of 32 dead people. LeVey’s findings had no basis, contradicted, never replicated in another study and LeVey is an admitted homosexual. Could he had vested interest in providing a genetic link, that some people are born homosexuals? Baily and Pillard study found that homosexuality is prone among twins. If one twin is a homosexual, the other twin should also be homosexual for monozygotic twins. This has never been proven. This study also received criticism because of the its choice of sample, which is siblings of homosexuals. Dean Hamer claimed to have found the “gay gene” in 1993, which was at X chromosome at position Xq28. His study had no controls. That is, he never proved the absence of the “gay gene” in heterosexual men. Secondly, his findings were never replicated. Dean Hamer was found to have forged the results of his findings by the NIHFRI. Hamer is also an admitted homosexual. He himself admitted that his research did not support a genetic cause for homosexuality, and that female homosexuality is “culturally transmitted” not “inherited”. In 1995 he continued to say “there is no single master gene that makes people gay”

Currently there is a renewed interest in searching for biological etiologies for homosexuality. However, to date, there are no scientific replicated studies supporting any specific biological etiology for homosexuality (American Psychiatric Association). Homosexuals are trying to prove that homosexuality is genetic, not a choice. In 2000, they did a study, saying that finger length has influence on homosexuality. In 2008, they did a study on eye blinking. Homosexuals do not produce offspring. How do these “gay genes” get transferred? Being a man with less testosterone does not mean one is supposed to be gay. It is obvious that homosexuals are trying by all means to find a genetic cause for homosexuality. They do this because they have suffered a long history of discrimination. Secondly, they are powerless to help themselves as a community. Thirdly, they are “born this way”. For homosexuals to be protected by Civil Rights Commissions fully, a genetic link or cause for homosexuality has got to be found.

To summarize, science has failed to prove the existence of a “gay gene”. Instead of that, science proved that gonadal steroid hormones act directly to promote sex differences. This says nothing about homosexuality. All it does is to support a widely accepted theory about hormones and gender. Although homosexual researchers such as Simon LeVey and Dean Hamer have laid a starting point for research on genetic linkage, a lot needs to be done. The issue of Caster Semenya is of this nature. She was born with internal testes and thus developed a homosexual behavior. Is homosexuality a choice? Is it a learnt attribute from interactions in the environment? If not, we have a long way to go in efforts to proving that it is genetic, which has not been proven to date.
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